1. Field of the Invention
This invention relates generally to the field of biomedical imaging. More specifically, the invention relates to imaging agents for functionally imaging the lymphatic system.
2. Background of the Invention
The lymphatic system is made of vessels or ducts that begin in tissues and are designed to carry lymph fluid to local lymph nodes where the fluid is filtered and processed and sent to the next lymph node down the line until the fluid reaches the thoracic duct where it enters the blood stream. Lymph vessels infiltrate all tissues and organs of the body. Lymph fluid is generated from capillaries, which because of tissue motion and hydrostatic pressure, enters the lymph vessels carrying with it local and foreign substances and materials from the tissues. These local and foreign molecular, micromolecular and macromolecular substances include antigens, infectious agents, particles and cells. Lymph nodes, the lymph “filters,”, consist of essentially two major compartments: the fluid spaces(or sinuses) and the cellular elements. There is one major sinus at the outer margin of the node that feeds a maze of sinuses that serve to percolate the fluid slowly towards the hilum of the node from where it is carried downstream. The sinuses are lined by macrophages that phagocytose materials carried by the fluid, particularly if the materials have certain surface charges or specific shapes. The remainder of the cellular elements in the lymph node performs the immunologic function of the node. In this regard, the lymph nodes process fluid by sieving and phagocytosis to remove particulate and cell materials delivered by the lymphatic vessels, thereby cleaning it before it is returned to the blood stream.
The lymph system plays an important part of health and disease. In cancer, the lymphatic system plays an important role in metastasis, or the dissemination of cancer cells throughout the body. It is thought that cancer cells first spread through the lymph system before disseminating through out the body. As a result, patients diagnosed with many forms of cancer undergo nodal staging, in which lymph nodes are surgically resected for pathological examination of cancer cells. Often, the resection of lymph nodes for staging purposes has deleterious effects. Upon removing lymph nodes, the lymphatic system is disrupted, leading to lymphedema. Lymphedema is a lifelong condition progressing from swelling and scarring to immune dysregulation and malnutrition. The onset of symptoms, however, can occur from days, weeks, to years following the initial trauma, striking at a rate cited between 6 and 62.5% of breast cancer survivors who have undergone axillary lymph node dissection, up to 64% of all patients who undergo groin dissections, and 25% of all radical hysterectomy patients. Little is known about the molecular or functional basis of acquired lymphedema or which persons could be at risk for the condition. As a result, surgeons seek to resect the first draining or “sentinel” lymph node that drains a tumor lesion in order to minimally disrupt the lymphatic system. Often the “sentinel” lymph node is difficult to detect and therefore resect. For example, in colon cancer, surgeons often have a difficult time finding lymph nodes that line fatty colon. Since metastastic colon cancer has a low survival rate, it is especially important to find as many nodes as possible in resected colon in order to improve the accuracy of determining whether there has been cancer spread. While there are non-specific imaging agents to drain through lymph nodes to provide possible identification of “sentinel” lymph nodes, there are few approaches is molecularly “tag” lymph nodes for efficient identification at surgery.
The ability to functionally image the lymphatic system non-invasively may be clinically relevant for the prevention, diagnosis, treatment, and research of lymphatic diseases, including cancer. However, there are presently very few technologies with the ability to non-invasively image the lymphatic system and lymph nodes in vivo and in real time.
Consequently, there is a need for imaging methods and imaging agents for dynamically assessing lymph function in vivo both non-invasively and intraoperatively.